PROJECT SUMMARY AND ABSTRACT CANDIDATE: I am a postdoctoral research fellow in Dr. Omar Abdel-Wahab's laboratory at the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center. My current research focuses on pathogenesis and therapy of splicing factor mutations in leukemias. We previously demonstrated that spliceosome-mutant leukemias are more susceptible to splicing modulatory compounds than wildtype leukemia. Extending from these observations, we are now systematically defining previously unknown genetic dependencies in spliceosome mutant leukemias to identify actionable targets that can be translated clinically. The proposed research will form a solid platform from which I can establish my own research group by the end of the K99 Award period. My long-term career goal is to establish a research program focusing on the molecular regulation of normal and malignant hematopoiesis, with a strong commitment to translate basic scientific discoveries into the clinic. I have developed a focused training plan to ensure my success to becoming an independent investigator: (1) broaden my scientific scope and experimental skillsets; (2) enhance leadership potential and professional development; (3) establish an independent committee to oversee on my training progress, and (4) transition into tenure-track research independence in the R00 phase. RESEARCH: Acquired mutations in genes encoding the RNA splicing factors SF3B1, SRSF2 and U2AF1 represent the most prevalent class of genetic alterations in leukemias. These mutations occur as heterozygous point mutations at specific hot-spots and confer functional alterations in RNA splicing. With the exception of MDS-RARS patients, spliceosome mutations in myeloid leukemias are correlated with poor clinical outcome. Although we have previously shown that spliceosome-mutant leukemias are more susceptible to pharmacologic modulation of splicing, additional vulnerabilities in mutant leukemias are unknown. We aim to define the genetic dependencies unique to spliceosome mutant leukemias. The Specific Aims are: (1) identify the mechanistic basis for mutual exclusivity of spliceosome mutations in leukemias, (2) define novel genetic dependencies specific to spliceosome mutant leukemias, and (3) investigate the role of mutant SF3B1- mediated MAP3K7 mis-splicing in the pathogenesis and therapy of leukemia. ENVIRONMENT: As a member of the Abdel-Wahab laboratory, we are part of the Human Oncology and Pathogenesis Program (HOPP) at MSKCC, a department that specializes in mechanism-based research to advance clinical translation. Under the leadership of Dr. Charles Sawyers, HOPP is known for its highly collaborative environment to facilitate translational research efforts such as those proposed in this application.